6-fluoro-6-dehydropregnan compounds



United States Patent ()fiice amass Fatented Feb. 1, 1966 3,232,966 6-FLUOR0-6-DEHYDROPREGNAN CGMPQUNDS Howard J. Ringold, Albert Bowers, Octavio Mancera, and George Rosenlkranz, Mexico City, Mexico, assignors, by mesne assignments, to Syntex Corporation, a corporation of Panama No Drawing. Filed Aug. 14, 1958, Scr. No. 754,923 Claims priority, application Mexico, Aug. 16, 1957,

48,57 28 Claims. c1. zen-397.45

.for the production of the aforementioned triene derivatives. The present invention also relates to 21-monoesters of the aforementioned compounds of hydrocarbon carboxylic acids of less than 12 carbon atoms.

In our US. patent application Serial No. 740,550, now US. Patent No. 2,934,546 filed June 9, 1958, and Serial No. 749,652, now US. Patent No. 2,951,840 filed July 21, 1958, there is disclosed the potent cortical hormones 60rfluoro-A -pregnen-17a,2l-diol 3,11,20 trione and 60efiuoro-N-pregnen-l1,8,17a,2l-triol-3,20-dione as well as derivatives of these compounds having a 9u-fiuoro group and their esters.

In accordance with the present invention it has been discovered that the aforementioned compounds and desirably the 2l-esters thereof are intermediates for the production of the corresponding A and A compounds of the present invention by dehydration thereof to provide an additional double bond in the C4( 6) or both the C-1 (2) and C-6(7) positions. The resultant compounds having the M' -structure are intermediates for the production of the corresponding A -compounds and these last compounds are valuable hormones of the cortical type having an anti-inflammatory activity higher than the corresponding M-compounds as well as lesser side reactions such as sodium retention.

The novel potent cortical compounds of the present invention having in their molecule a -fluorine may be characterized by the following formulas:

CIIEOR Y represents hydrogen, chlorine or fluorine. R represents hydrogen or a hydrocarbon carboxylic acid acyl group of less than 12 carbon atoms. These ester groups as known in the steroid art may be saturated or unsaturated, straight or branched chain aliphatic, cyclic or cyclicaliphatic and may be conventionally substituted as by methoxy or halogen. Typical acyl groups are acetate, propionate, butyrate, hemisuccinate, caproate, benzoate, trimethylacetate, cyclopentylpropionate, phenoxypropionate and B-chloropropionate. All of the above compounds are cortical type hormones having a high anti-inflammatory activity together with a minimum of undesirable side effects.

The novel compounds of the present invention are prepared by a process outlined in the following equation:

(EHzOR 0112013.

00 ---orr chloranil 03 xylene O: V

l I F F \chloranil selenium dioxide l n-amyl or chloranil and alcohol n-amyl alcohol l O O H X X ehloranil 1 1 1 a co .0 or O xylene O l F F In the above equation X, Y and R represent the same groups as heretofore set forth.

The preferred starting material is one where R represents the acetate radical as for example the Zl-rnouoacetate of the starting materials indicated. Refluxing with selenium dioxide preferably in admixture with t-butanol in the presence of pyridine gave the corresponding diene compounds, and refluxing these dienes with chloranil in n-amyl alcohoi or Xylene gave the corresponding acetates of A -trienes. These last compounds were also obtained directly from the A startin materials by refluxing with chloranil in n-amyl alcohol. Refiuxing the A starting compounds with chloranil in Xylene however, produced the M' -derivatives indicated which could be transformed to the A -derivatives by a second treatment with chloranil in n-amyl alcohol or by refluxing with selenium dioxide. As may be understood, other esters of the type previously set forth may be used instead of the acetates and the A, A and A ester compounds prepared may be conventionally saponified and reesterified.

The following specific examples serve to illustrate out are not intended to limit the present invention.

Example I A mixture of 1.5 g. of the 2l-acetate of 6a-fluoro-cortisone, 2 g. of chloranil and 30 cc. of anhydrous n-amyl alcohol was refluxed for 16 hours, cooled and diluted with ether; the solution was washed with water, 5% sodium carbonate solution and Water, dried over anhydrous sodiurn sulfate, filtered and evaporated to dryness. Chromatography of the residue on ethyl acetate washed alumina yielded the ZI-acetate of 6tluoro-A pregnatrien-:, 21diol-3,1l,20-trionc.

Example 11 1 g. of the ZI-acetate of 6e-fiuoro-9ot-chloro-A -pregnen-l1/3,17u,2l-triol 3,20--dione was mixed with 1.6 g. of

chloranii and 40 cc. of xylene and refluxed for 12 hours. The cooled mixture was diluted with ether, washed with water, 5% sodium carbonate solution and water to neutral, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Chromatography of the residue on ethyl acetate washed alumina furnished the ZI-acetate of 6-fiuore-9a,chloro-A -pregnadien-l1,6,17ot,21-triol-3,20-dione.

A mixture of 1 g. of the Zhacetate of 6-fiuoro-9uchloro-M -pregnadien-i1B,l7a,2l-triol-3,20 dione, 50 cc. of anhydrous t-butan-ol, 300 mg. of selenium dioxide and 0.2 cc. of pyridine was refluxed for 70 hours under an atmosphere of nitrogen, diluted with ethyl acetate and filtered through celite, washing the filter with hot ethyl acetate. The combined filtrate and washings was evaporated to dryness under reduced pressure and the residue was triturated with water and collected by filtration, dried and chromatographed on neutral alumina. There was thus obtained the 21-acetate of 6-fillO1O-9Ot-ChlO1'O-A pregnatrien-l1,6,17m,21-triol-3,20-dione.

Example III A mixture of 1 g. of the 2l-aoetate of 6e,9a-difluoro- A -pregnadien-17o ,21-di0l-3,11,2O-trione, 1.5 g. of chloranil and 20 cc. of n-amyl alcohol was refluxed for 12 hours and the reaction product was then worked up as described in Example I, thus giving the 2l-acetate of 6,904- difluoro A pregnatrien 17c:,21-diol-3,11,20-trione. In another experiment, the n-amyl alcohol was substituted by xylene, with the same result.

Example IV 1 g. of the ZI-acetate of 6-fluoro-A -pregnatrien 17a,21-diol-3,11,20-trione, obtained in accordance with the method of Example I, was mixed with 20 cc. of anhydrous methanol, cooled to C. and slowly treated with stirring with a cooled solution of sodium methoxide prepared by dissolving 70 mg. of sodium in 5 cc. of anhydrous methanol; the stirring was continued for half an hour under an atmosphere of nitrogen and then the mixture was acidified with a few drops of acetic acid and poured into ice water. The precipitate was collected, dried and recrystallized from acetone-hexane, thus aifording the free 6-fluoro-A -pregnatrien-1M21-diol-3,11,20- trione.

By the same method from the 21-acetates of 6-fiuoro- 9e-chloro-A -pregnadien-11,8,17c4,21-triol-3,2O-dione and 6 fiuoro 9m chloro-A -pregnatrien-11fl,17ot,21-triol- 3,20-dione of Example II there were obtained the corresponding free compounds. Similarly the 21-acetate group of 6,9tz difluoro A -pregnatrien-17a,21-diol-3,11,20- trione of Example III was converted to a free hydroxyl.

Example V A mixture of 1 g. of 6-fluoro-A -pregnatrien-l7a,2i diol-3,11,20-trione, obtained in accordance with the previous example, 20 cc. of pyridine and 1 cc. of propionic anhydride was kept overnight at room temperature and then poured into Water. The reaction product was extracted with ethyl acetate, washed with Water, dilute hydrochloric acid, Water, 5% sodium carbonate solution and finally again with water, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization of the residue from acetone-hexane yield-ed the 2l-propionate of 6-fiuoro-A -pregnatrien-l7ot,2l-diol-3,11,20-trione.

By the same method all of the other free alcohols of Example IV were converted to the corresponding 21- monopropionates. Using other corresponding acid anhydrides or chlorides by the same conventional esterification there were also prepared the corresponding benzoates, cyclopentylpropionates as well as other hydrocarbon carboxylic esters of less than 12 carbon atoms.

Y I/ O:

wherein X is selected from the group consisting of 0 and Y is selected from the group consisting of hydrogen, chlorine and fluorine and R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of up to 12 carbon atoms.

2. 6-lluoro-A -pregnadien-17 ot,2l-CllOl-3,l1,20-1IlOI16.

3. The 21-mono hydrocarbon carboxylic acid esters of up to 12 carbon atoms of 6-fiuoro-A -pregnadien-17,2ldiol-3,1 1,20-trione.

4. 6,9 difiuoro A pregnadien 17a,21 diol- 3,11,20-trione.

5. The 2l-mono hydrocarbon carboxylic acid esters of up to 12 carbon atoms of 6,9a-difluoro-A -pregnadienl7ot,2l-diol-3,l1,20-trione.

6. 6 fluoro chloro A pregnadien 17a,21- diol-3,11,20-trione.

7. The 2l-mono hydrocarbon carboxylic acid esters of up to 12 carbon atoms of 6-fluoro-9a-chIOrO-M' -pregnadien-17ot,2l-diol-3,11,20-trione.

8. 6 fluoro A pregnadien 11,8,17a,2l triol- 3,20-dione.

9. The 21-mono hydrocarbon carboxylic acid esters of up to 12 carbon atoms of 6 -iluoro A pregnadienl1B,17u,21-triol-3,20-dione.

1i 6,9ot difluoro A pregnadien 1l,8,17a,2l-triol- 3,20-dione.

11. The 2l-mono hydrocarbon carboxylic acid esters of up to 12 carbon atoms of 6,9a-difluoro-A pregnadien- 1 1p,17ot,21-trio1-3,20-dione.

12. 6 fluoro 9a chloro-M -pregnadien-11B,17a,21- triol-3,20-dione.

13. The 2l-rnono hydrocarbon carboxylic acid esters of up to 12 carbon atoms of 6-fluoro-9a-cl1ioro-A -pregna dien-l l5,17ot,2l-triol-3,2t)-dione.

14. Compounds of the following formula:

CHzOR wherein X is selected from the group consisting of :0 and Y is selected from the group consisting of hydrogen,

chlorine and fluorine and R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of up to 12 carbon atoms.

15. 6 fiuoro A pregnatrien 17a,2l'dlOl3,l1,20- trione.

16. The 21-mono hydrocarbon carboxylic acid esters of up to 12 carbon atoms of 6-fiuoro-A -pregnatrien- 17a,21-dlOl3,11,20-t1i0113.

17. 6,901 diiiuoro A pregnatrien 17a,21 diol- 3,11,20trione.

18. The 2l-rnono hydrocarbon carboxylic acid esters of up to 12 carbon atoms of 6,9e-difiuoro-A -pregnatrien- 17a,21-diol-3,11,20-trione.

19. 6 fiuoro 90c chloro A pregnatrien 17,21- dio1-3, 1 1,2CI-trione.

20. The 21-mono hydrocarbon carboxylic acid esters of up to 12 carbon atoms of 6-fiuoro-9u-chloro-A -pregnatriene-17a,21-diol-3,11,20-trione.

21. 6 fluoro A pregnatrien 1lfl,17a,21 triol- 3,2fi dione.

22. The 21-mono hydrocarbon carboxylic acid esters of up to 12 carbon atoms of 6-flnoro-A -pregnatrienl1B,17a,21-triol-3,20-dione.

23. 6,911 difiuoro A pregnatrien 11B,17a,21- triol-3,20-dione.

24. The 21-rnono hydrocarbon carboxylic acid esters of up to 12 carbon atoms of 6,9ca-difiuoro-A -pregnatrien- 11,8,17a,21-triol-3,20-dione.

25. 6 fluoro 9a-chloro-A -pregnatrien-11p,17ot,21- trioi-3,20-dione.

26. The 2l-rnono hydrocarbon carboxylic acid esters of up to 12 carbon atoms of 6-fluoro9wchloro-N pregnatrien-l1B,17a,21-triol-3,20-dione.

27. A compound of the formula:

CH2OR wherein the 1,2 carbon atom linkage is selected from the group consisting of single bond and doubled bond linkages, wherein Z is selected from the group consisting of 6 the carbonyl radical C O) and the fi-hydroxy methylene radical and R is selected from the group consisting of hydrogen and hydrocarbon acyl group of up to 4 carbon atoms.

28. A compound of the formula:

(II-R wherein the 1,2 carbon atom linkage is selected from the group consisting of single bond and double bond linkages, G is selected from the group consisting of hydrogen and fluorine, Z is selected from the group consisting of the carbonyl radical C O) and the and R is selected from the group consisting of hydrogen and a hydrocarbon acyl group of up to 12 carbon atoms.

References Cited by the Examiner UNETED STATES PATENTS 2,838,548 6/1958 Magerlein et a1. 260397.45 2,841,600 7/1958 Hogg et al. 260397.45 2,877,239 3/1959 Agnello et a1. 260-397.4 2,881,168 4/1959 Spero 260239.55 2,882,282 4/1959 Agnello et a1. 26G397.3

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,232,966 February 1, 1966 Howard J. Ringold etala It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 2, lines 25 to 35, the left-hand fiormula should appear as shown below instead of as in the patent:

(SEAL) Attest:

EDWARD J. BRENNER ERNEST W. SWIDER Commissioner of Patents Attesting Officer 

1. COMPOUNDS OF THE FOLLOWING FORMULA: 